This application addresses the critical need for efficacious non-pharmacological treatments for human immunodeficiency virus type 1 (HIV) sensory neuropathy (HIV-SN). This neuropathy can be associated with viral infection alone, likely involving a role for the envelope glycoprotein gp120; or a drug-induced toxic neuropathy associated with the use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) as a component of highly active anti-retroviral therapy. Dr. Mohab Ibrahim, Principal Investigator on this project, along with Dr. Rajesh Khanna, a co-Investigator on this project, first showed that low intensity green light provided long-lasting antinociception in nave animals. No side-effects were noted and motor performance was not impaired. The antinociception may be due to increased endogenous opioid expression observed in the spinal cord and possibly the decrease in inflammatory factors. Their recent work also demonstrated reversal of mechanical and thermal hypersensitivity in rats subjected to spinal nerve ligation? a model of chronic neuropathic pain. Thus, understanding the mechanisms that contribute to green light mediated antinociception would be a critical first step in developing this as a novel form of therapy. We will test our hypothesis that exposure to green light will reduce thermal, mechanical hypersensitivity due to engagement of the endogenous opioid system and decrease inflammatory mediators. We will test this hypothesis with four related, but independent, specific aims using the envelope glycoprotein gp120 model of HIV-induced painful peripheral neuropathy. We will first determine the time-course and light intensity (lux levels) needed for reversal of thermal and mechanical hypersensitivity in the gp120 model of HIV-induced painful peripheral neuropathy and the mechanical hypersensitivity associated with antiretroviral therapy (SA1). Next, we will determine the contribution of the endogenous opioid system in mediating the effects of green light emitting diode (GLED) and whether a fixed light intensity/duration along with a mu opioid receptor agonist or a non opioid neuropathic pain medication such as gabapentin result in a synergistic antinociceptive effect in animals with gp120-induced neuropathy (SA2). We will characterize cellular activation and determine the levels of inflammatory cytokines in the spinal cord dorsal horn, brain, cerebrospinal fluid, and plasma from rats with gp120-induced neuropathy and following GLED exposure (SA3). Finally, we will investigate possible side effects that may be associated with prolonged exposure to green light therapy in preparation for introducing this therapy to human patients (SA4). Green light therapy resulting in decreased chronic pain without side effects has the promise of being easily translatable into the clinic due to their apparent efficacy, safety, low cost and availability. Our studies may offer an adjunct to current clinical therapies likely resulting in reducing opioids to manage HIV induced neuropathic pain, as well as other chronic pain states. Importantly, with a reduction in their pain, HIV patients may be more compliant with their antiretroviral therapy.